Interleukin 15 (IL-15), discovered by Grabstein et al. in 1994, is a cytokine of about 12-14 kD, which plays a role in the normal immune response in organisms, such as promoting the proliferation of T cells, B cells and natural killer (NK) cells.
IL-15 is a member of the small four α-helix bundle family of cytokines. IL-15 needs to bind with its receptor to exert its biological activity. IL-15 receptor consists of three receptor subunits: IL-15 receptor α (IL-15Rα), IL-2 receptor β (IL-2Rβ, also known as IL-15Rβ or CD122) and γc (also known as CD132). IL-15Rα contains a Sushi domain which is capable of binding with IL-15, and is essential for biological functions of IL-15 after binding.
Recently, it was found that the complex formed by IL-15 and its receptor IL-15Rα can significantly enhance the biological activity of IL-15. Studies indicated that the complex formed by IL-15 and soluble IL-15Rα receptor is significantly superior to IL-15 alone in stimulating the proliferation of memory CD8+ T lymphocytes and NT/NKT cells. IL-15/IL-15Rα complex is more than 10 times stronger than IL-15 alone in stimulating proliferation of memory CD8+ T cells and in maintaining their survival. The mechanism may be related to cis presentation.
Since it has been demonstrated that IL-15 is expected to be useful in the field of tumor immunotherapy, the National Institutes of Health (NIH) first began investigating IL-15 treatment in the tumor area, and tried to push it into Phase I clinicals. However, IL-15 has the disadvantages of small molecular weight, short in vivo half-life, hardly-controlled repeated dosage, and is likely to cause systemic immune side effects. There is an urgent need to find an approach which can increase the in vivo half-life, and promote or enhance the biological activity of IL-15 in vivo. There are many domestic and foreign companies or research institutions engaging in research related to IL-15 immunotherapy. For example, Chinese Patent CN100334112C (Shanghai Haixin Biotechnology Co., Ltd.) relates to IL-15-hIgG4Fc homodimeric protein in anti-microbial infection treatment; Chines Patent Application CN1942481A (Switzerland F. Hoffmann-LaRoche AG) relates to IL-15-Fc fusion expression system and its use; and Chinese Patent CN101360827B (French Institute of Health and Medical Research) relates to IL-15Rα (sushi+domain)-IL-15 fusion protein and its application in cancer treatment. Heterodimeric molecules of the present application show better stability, prolonged in vivo half-life and improved biological activity by increasing intramolecular interactions. On the basis of the molecular design in the present application, targeting immune cytokines can be generated by fusing and inserting functional polypeptides via methods well known in the field. The present disclosure also relates to the application of targeting immune cytokines in cancer and autoimmune disease therapy.